(s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations

ABSTRACT

A composition comprising (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide and hypromellose acetate succinate for pharmaceutical preparations, especially capsule preparations.

BACKGROUND OF THE INVENTION

WO2009/105500 describes ERK inhibitors, including procedures for makingthem and procedures for preparing pharmaceutical compositions comprisingthe ERK inhibitors. Described pharmaceutical compositions include solidform preparations including powders, tablets, dispersible granules,capsules, cachets and suppositories for direct administration to apatient; liquid form preparations including solutions, suspensions andemulsions for direct administration to a patient; aerosol preparationssuitable for inhalation; solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations, includingsolutions, suspensions and emulsions for subsequent administration to apatient; and transdermal compositions including creams, lotions,aerosols and/or emulsions for direct application to the patient oradministration via transdermal patch.

(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide,a specific ERK inhibitor described in WO2009/105500, is most stable incrystalline hydrate Form 2. This form has poor solubility, and in orderto efficiently prepare certain pharmaceutical compositions foradministration to patients including tablet and capsules suitable forsafe and effective oral administration, it is highly desirable to createamorphous dispersions to improve solubility wherein the amorphous formof the drug shall have higher apparent solubility compared to itscrystalline counterparts.

The present invention provides a dispersion of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidehaving improved solubility which allows for efficient preparation oftablets and capsules suitable for safe and effective oral administrationto a patient.

SUMMARY OF THE INVENTION

The invention is a composition comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand hypromellose acetate succinate, methods for preparing thecomposition, and uses of the composition to prepare pharmaceuticalpreparations, including capsule preparations, for administration to apatient.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is graph of Powder X-Ray Diffraction Data associated with(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideFree Base Hydrate Form 2.

FIG. 2 is graph of Powder X-Ray Diffraction Data associated with(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideHCl Form 1.

FIG. 3 is graph of Powder X-Ray Diffraction Data associated with(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideHCl Hydrate Form 1.

FIG. 4 is graph of Powder X-Ray Diffraction Data associated with(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideHCl Hydrate Form 2.

DETAILED DESCRIPTION OF THE INVENTION

The invention is a composition comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand hypromellose acetate succinate.

In one embodiment, the composition comprises(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand hypromellose acetate succinate, wherein the weight ratio of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideto hypromellose acetate succinate is between about 1:1 and 1:5. Inanother embodiment, the weight ratio is about 1:3.

The invention is also a film cast process for preparing a hard gelatincapsule comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidewhich comprises the steps of

a) dissolving(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidefree base hydrate form 2 and hypromellose acetate succinate in a solventto form a solution,

b) evaporating the solvent from the solution to form a film castcomprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form;

c) grinding the film cast to form a ground product.

The ground products can then be used to fill a hard gelatin capsule or ahydroxypropyl methylcellulose capsule or formulated into a tablet usingconventional tableting procedures.

In an embodiment of the film cast process, the weight ratio of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideto hypromellose acetate succinate is between about 1:1 and 1:5. Inanother embodiment of the film cast process, the ratio is about 1:3. Inanother embodiment of the film cast process, the solvent is acetone.

The invention is also a hot melt extrusion process for preparing a hardgelatin capsule comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidewhich comprises the steps of

a) blending(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidefree base hydrate form 2 and hypromellose acetate succinate to form ablend,

b) extruding the blend through a twin screw hot melt extruder to form anextrudate,

c) quenching the extrudate on an air cooled conveyor belt or using achilled roller to form quenched extrudate comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form,

d) pelletizing the extrudate to form pellets and subsequently millingthe pellets to form a ground product.

The ground product can then be blended with a superdisintegrant whichcan then be filled into a hard gelatin capsule. Alternatively, thequenched extrudate can be pelletized, milled, sieved and then used toform a tablet using conventional tableting procedures.

In an embodiment of the hot melt extrusion process, the weight ratio of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideto hypromellose acetate succinate is between about 1:1 and 1:5. Inanother embodiment, the ratio is about 1:3.

Hypromellose acetate succinate used in the above processes can be ingranular form or fine powder. Various grades are suitable includinggrade M which has a pH sensitivity of ≧6.0; grade L which has a pHsensitivity of ≧5.5, and grade H which has a pH sensitivity of ≧6.8.Superdisintegrant can be crospovidone.

The invention is also a compound form of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideselected from Free Base Hydrate Form 2, HCl Form 1, HCl Hydrate Form 1,and HCl Hydrate Form 2. In an embodiment of the invention the form isFree Base Hydrate Form 2. In an embodiment of the invention the form isHCl Form 1. In an embodiment of the invention the form is HCl HydrateForm 1. In an embodiment of the invention the form is HCl Hydrate Form2.

(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide,structure I below:

and method for its preparation, is described in patent publicationWO2009/105500 (compound A6).(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideis also available from Active Biochem CAT# A-1191. The compound, whichinhibits ERK activity (i.e., ERK1 and ERK2 activity), may be useful fortreating a broad spectrum of cancers, such as, for example, melanoma,pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer,breast cancer, and ovarian cancer.

Preparation:

(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidefree base synthesis is 19 steps. Compound preparation is divided intothree intermediate preparations A, B and C followed by coupling of theintermediates. All intermediates start with commercially availablecompounds. Compound 5 is prepared by reaction of the commerciallyavailable bromo-4-cyanobenzene with methyl hydrazine under acidicconditions to form the hydrazinoimidate 2 in modest yield. Afterreaction with formic acid in two steps the bromophenyl-N-methyl triazoleintermediate 3 is obtained. The tetrahydropyridine ring is introduced bya Suzuki reaction of the commercially available Boc protectedtetrahydropyridine-boronate to obtain the tricyclic ring system 4.Chloroacetamide 5 is obtained in excellent yield by reaction of thedeprotected 4 with chloroacetylchloride. The pyrrolidine core 10a isobtained in good yield in 5 steps starting from commercially available6. Reaction with thionylchloride gave the thiomethyl olefin 7.Cycloaddition (2+3) gave 8 followed by removal of the benzyl protectiongroup to give 9. L-Tartaric acid resolution of the pyrrolidine coregives the pure (S) enantiomer 9 after filtration from methanol. Afterprotection as the Boc derivative and hydrolysis of the methyl ester, 10is obtain in overall 50% yield. Compound 17 is obtained fromcommercially available indazole 11. Bromination at the 3-position ofindazole 11 proceeded in excellent yield without chromatography toobtain 12. Suzuki reaction of the bromo compound 12 with 14 gave thenitro indazole 16 after chromatography. Reduction of 16 gave aniline 17as an oil in quantitative yield without chromatography. The finalcoupling of the intermediates proceeded by coupling 17 with 10a toobtain 18 in good yield. After deprotection of the Boc and Trityl groupsthe final coupling with 5 gave(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideafter chromatography. Final purification was carried out bycrystallization from methanol/diethylether. This synthetic route hasbeen conducted on a scale that delivered(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidefree base (Compound I).

Synthesis from Key Intermediates 5, 10 and 17

Preparation A:

Preparation B:

Preparation C:

Final Coupling:

Preparation of Free Base Hydrate Form 2

Compound I was suspended in neat water at ambient temperature. Mixturewas aged for at least one day yielding a crystalline form (Free BaseHydrate Form 2).

Preparation of HCl Form 1

HCl Hydrate Form 1 or HCl Hydrate Form 2 was suspended in ethyl acetate,toluene, acetonitrile, isopropyl acetate, acetone or tetrahydrofuran(THF) at ambient temperature. Mixtures were aged for at least one dayyielding a crystalline form (HCl Form 1).

Preparation of HCl Hydrate Form 1

Compound I was suspended in aqueous isopropanol mixtures followed by theaddition of hydrochloric acid. Mixtures were aged at ambient temperaturefor at least one day yielding a crystalline salt (HCl Hydrate Form 1).

Preparation of HCl Hydrate Form 2

Compound I was suspended in aqueous acetone mixtures followed by theaddition of hydrochloric acid. Mixtures were aged at ambient temperaturefor at least one day yielding a crystalline salt (HCl Hydrate Form 2).

HCl Form 1 was suspended in neat water at ambient temperature. Mixturewas aged for at least one day yielding a crystalline form (HCl HydrateForm 2).

Free Base Hydrate Form 2 Powder X-Ray Diffraction Data

2-θ, ° d-spacing, Å Relative Intensity, % 4.24 20.82 44 10.04 8.81 1912.78 6.92 49 13.48 6.57 7 14.22 6.23 14 14.98 5.91 30 15.79 5.61 2616.76 5.29 29 17.92 4.95 82 18.89 4.70 100 19.70 4.51 49 20.41 4.35 7420.76 4.28 87 21.26 4.18 56 22.16 4.01 40 22.85 3.89 16 24.88 3.58 1125.75 3.46 18 26.85 3.32 8 28.16 3.17 14 28.67 3.11 13 29.37 3.04 531.52 2.84 8 33.60 2.67 2 34.50 2.60 3 37.72 2.39 3

HCl Form 1 Powder X-Ray Diffraction Data

2-θ, ° d-spacing, Å Relative Intensity, % 3.99 22.14 100 7.08 12.49 88.44 10.48 6 9.39 9.42 53 11.95 7.41 46 14.14 6.26 24 14.80 5.99 3715.17 5.84 46 16.00 5.54 71 16.51 5.37 32 17.78 4.99 67 18.12 4.90 2018.81 4.72 75 19.22 4.62 31 20.20 4.40 61 21.02 4.23 29 21.55 4.12 3021.85 4.07 17 22.37 3.97 8 23.05 3.86 32 23.31 3.82 34 24.12 3.69 1625.59 3.48 21 26.34 3.38 18 26.85 3.32 12 28.73 3.11 15 29.17 3.06 1229.81 3.00 13 30.17 2.96 11 31.35 2.85 10 33.21 2.70 4 34.84 2.58 336.42 2.47 2

HCl Hydrate Form 1 Powder X-Ray Diffraction Data

2-θ, ° d-spacing, Å Relative Intensity, % 4.34 20.38 16 5.31 16.63 26.57 13.45 9 7.20 12.28 3 8.79 10.07 3 9.93 8.91 11 10.76 8.22 7 11.257.87 9 12.03 7.36 3 13.39 6.61 25 14.12 6.27 32 14.67 6.04 41 15.38 5.7614 16.22 5.46 21 17.31 5.12 59 18.17 4.88 43 19.08 4.65 54 19.41 4.57 6720.21 4.39 100 21.42 4.15 45 22.58 3.94 63 23.77 3.74 33 24.50 3.63 1226.11 3.41 35 27.51 3.24 28 28.25 3.16 15 29.57 3.02 13 30.61 2.92 1431.47 2.84 14 32.70 2.74 7 38.69 2.33 5

HCl Hydrate Form 2 Powder X-Ray Diffraction Data

2-θ, ° d-spacing, Å Relative Intensity, % 4.53 19.49 15 7.07 12.51 39.10 9.72 5 10.69 8.27 15 11.24 7.87 18 13.76 6.44 12 14.29 6.20 2714.58 6.08 28 15.03 5.90 30 16.60 5.34 22 17.16 5.17 23 17.59 5.04 4218.31 4.85 58 18.95 4.68 21 20.20 4.40 100 21.17 4.20 41 22.01 4.04 4223.05 3.86 41 23.57 3.78 27 25.65 3.47 27 26.99 3.30 14 27.81 3.21 1828.53 3.13 15 29.24 3.05 16 31.07 2.88 9 32.25 2.78 8 33.44 2.68 6 35.262.55 4 36.85 2.44 2

Film Cast Process

Film casting method can be used as preliminary screening technique todetermine the right amount of drug-polymer or plasticizer combinationthat can yield molecularly dispersed drug. Briefly, the drug and thepolymer are dissolved in different ratios in a common solvent havingadequate drug polymer solubility/mixture of solvents followed by filmformation on a glass surface by evaporation of the solvent at 24° C. for24 hours to remove residual solvent in the film cast that can otherwiseaffect the stability of the solid dispersion. A volatile solvent ispreferred over water or high boiling point solvents as the solvent wouldtake longer time to evaporate and there is a possibility of incompletedrying of the film. The film is subsequently pulverized using a mortarand pestle and sieved to get solid dispersion of appropriate size whichis then filled into capsules. The pulverized film is analyzed for itsamorphous nature via DSC, XRD and other analytical tools.

Hot Melt Extrusion Process

Solid dispersions of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecan be created using an extrusion process such as a hot melt extrusionprocess. Briefly,(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidehydrate Form 2 (DS) and a polymer such as hypromellose acetate succinateare blended in a mixer such as a Turbula mixer in a DS:polymer weightratio between about 1:1 and 1:5 followed by feeding of the powdermixture using a vibration feeder to an extruder such as the LeistritzNano 16 mm twin screw extruder. The drug polymer blend is extruded andresulting extrudate is quenched in, for example, liquid nitrogen, andsubsequently milled using a grinder. The milled extrudate is sieved andblended extragranularly with a superdisntegrant such as crospovidone at10% w/w of the extrudate for 5 minutes using a mixer such as a Turbulamixer, and the extrudate/disintegrant blend is subsequently used toprepare a pharmaceutical formulation such as a hard gelatin capsule byfilling the capsule.

The solid dispersion composition prepared either via a film cast methodor hot melt extrusion results in the formation of an amorphous form,which after grinding is filled into the capsules and is the desirableform leading to solubilization enhancement for enhancing drugbioavailability.

Tablets comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form prepared via film casting or hot melt extrusion can beformed using conventional tableting procedures and vehicles and otherexcipients including diluents (such as lactose, avicel, mannitol,dibasic calcium phosphate) disintegrants (such as croscarmellose sodium,crospovidone, sodium starch glycollate), salt disintegrants (such asNaCl, NaHCO₃, KH₂PO₄, K₂SO₄, KCl), binders (such as povidone,hydroxypropyl methylcellulose, hydroxypropyl cellulose), glidants/flowpromoters (such as silicon di-oxide), lubricants (magnesium stearate,sodium stearyl fumarate) and anti-oxidants (for example BHT, BHA, propylgallate) to improve the chemical stability of the formulation.

The absence of the crystalline peaks, as evidenced by XRD analysis,indicated that(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidewas amorphous in the solid dispersion formulation. DSC thermogram of thesolid dispersion formulation showed a Tg of 110° C. which signifiesphysical stability. The absence of a melting endotherm at 133° C. (themelting point of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidehydrate Form 2 is 133° C.) also indicated that(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideis amorphous in the solid dispersion formulation.

Example 1 Solid Dispersions of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideExample 1a—Film Cast Process

Films of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidesolid dispersion with hypromellose acetate succinate were prepared viasolvent casting technique according to the following procedure:

Step 1:(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2 (HF-2) and the granular polymer hypromelloseacetate succinate grade M was dissolved in acetone in a 1:3 (% w/w)ratio (drug load 25%) followed by evaporation of the solvent followed byvacuum drying of the film cast to further remove any residual solvent.Step 2: The film casts were crushed/grinded and sieved through a #16mesh.

The crushed dispersion was subsequently filled into a size 00 hardgelation capsule. 100 mg(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand 300 mg of hypromellose acetate succinate were loaded into a capsule.

The solid dispersion with hypromellose acetate succinate resulted insignificantly enhanced dissolution in a 2-stage dissolution study with a˜10 fold increase in exposure compared to the crystalline HF-2 at ˜50 mgdose. Furthermore, DSC data indicated good physical stability of thesolid dispersion with a Tg of 120° C.

Pre-clinical dog pharmacokinetic studies show that solid dispersionsprepared via film casting outperform other suspension-based formulationsof the(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidehydrate Form 2.

TABLE 1a Results of pre-clinical dog pharmacokinetic studies of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide Example 1a(50 mg dose) HF-2 hg HF-2 HF-2 np AF HPMCAS suspension suspensionsuspension Example 1a 50 mg/kg 50 mg/kg 43.1 mg/kg 44.6 mg/kg Dose MeanCV (%) Mean CV (%) Mean CV (%) Mean CV (%) Cmax 293 −75 365 −54 1820 −552730 −37 (ng/mL) Tmax (hr) 4 (1.5-6) 3 (2-4) 3 (2-6) 4 (2-4) AUC (24)2000 −77 2020 −74 12300 −78 17700 −39 ng-hr/mL AUC (I) 2.96 −78 2.95 −7317.9 −78 25.9  39 μM-hr t½ (hr) 2.26 −19 2.52 −30 9.03 −93 13.1 (NC)

“HF-2” is(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2. “AF” is(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form. “HPMCAS” is hypromellose acetate succinate. “hg” is handground. “np” is nanoparticle.

Example 1b—Hot Melt Extrusion Process

Hot melt extrusion formulations of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide(drug) with hypromellose acetate succinate (L and M grades with pHsensitivity of 5.5 and 6.0 respectively) were prepared at 25% drug loadusing a 16 mm Leistritz twin screw extruder with co-rotating screwsusing the following process conditions (barrel temp of ˜120-130 C);screw speed: −250 rpm and a 25:1 L/D configuration for the barrel.

(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2 and hypromellose acetate succinate wereblended in a Turbula mixer in a ratio of 1:3 (25% drug load) followed byfeeding of the powder mixture using a vibration feeder to the LeistritzNano 16 mm twin screw extruder. The drug polymer blend was extrudedusing the extrusion conditions as mentioned above. Following extrusion,the extrudate was quenched in liquid nitrogen and subsequently milledusing a grinder. The crushed extrudate was passed through a size 30mesh. The sieved extrudate was blended extragranularly withsuperdisintegrant crospovidone at 10% w/w of the extrudate for 5 minutesusing a Turbula mixer.

The extrudate and disintegrant blend subsequently filled into a size 00hard gelatin capsule. 100 mg(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide,300 mg hypromellose acetate succinate and 40 mg crospovidone were loadedinto a capsule.

Formulations prepared by extrusion significantly enhanced dissolution ofthe drug. In a 2-stage dissolution study, M grade was superior to Lgrade. The DSC analysis of the extrudates indicated good physicalstability displaying a Tg of ˜110° C. XRD analysis demonstrated lack ofcrystalline peaks, indicating the drug was amorphous for both thehypromellose acetate succinate M and hypromellose acetate succinate Lextrudate. Results of dog PK study of different(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideformulations at 50 mg/kg dose

Formulations prepared by hot melt extrusion resulted in an exposure thatwas 25-40 fold higher than(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2. Formulations prepared by hot melt extrusionalso resulted in an exposure that was 1.6 fold higher than the amorphoussuspension formulation of the drug. The formulation performance of thehot melt extrusion formulations was comparable to the(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2 HCL salt of the drug present as ablend/suspension form.

TABLE 1b Results of pre-clinical dog pharmacokinetic studies of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide Example 1b (50mg dose) AF AF HPMCAS-L HPMCAS-M HF-2 HCl HF-2 HCl capsule capsule AFsuspension suspension capsule Example 1b Example 1b 50 mg/kg 50 mg/kg 50mg/kg 58.8 mg/kg 55.5 mg/kg Dose Mean CV (%) Mean CV (%) Mean CV (%)Mean CV (%) Mean CV (%) Cmax (ng/mL) 4602 (34) 6490 (21) 4523 (30) 4367(54) 7056 (43) Tmax (hr) 4 (4-8) 4 (4-8) 8 (3-12) 6 (4-12) 6 (4-12) AUC(24) 47687 (41) 65750 (27) 57008 (46) 52244 (55) 85232 (39) ng-hr/mL AUC(I) 69.3 95.2 86.3 80.5 130 μM-hr t½ (hr) 1.89 (11) 2.25 (37) 2.62 NC3.71 (63) 4.89 (31)

“HF-2” is(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidecrystalline hydrate Form 2. “AF” is(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form. “HPMCAS L” is hypromellose acetate succinate grade L.“HPMCAS M” is hypromellose acetate succinate grade M. “CV (%)” iscoefficient of variation.

1. A composition comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand hypromellose acetate succinate.
 2. A composition of claim 1comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideand hypromellose acetate succinate, wherein the weight ratio of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideto hypromellose acetate succinate is between about 1:1 and 1:5.
 3. Acomposition of claim 2 wherein the weight ratio is about 1:3.
 4. Aprocess for preparing a composition of claim 1 which comprises the stepsof a) blending(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamidehydrate form 2 and hypromellose acetate succinate to form a blend, b)extruding the blend through a twin screw hot melt extruder to form anextrudate, c) quenching the extrudate on an air cooled conveyor belt orusing a chilled roller to form quenched extrudate comprising(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideamorphous form, d) pelletizing the extrudate to form pellets andsubsequently milling the pellets to form a ground product.
 5. A processof claim 4 wherein the weight ratio of(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamideto hypromellose acetate succinate is between about 1:1 and 1:5.
 6. Aprocess of claim 4 wherein the ratio is about 1:3.